# The Multiple Roles of Lysyl Oxidase in Arteriovenous Fistula Failure

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2021 · —

## Abstract

More than 14 000 enrolled veterans depend on an arteriovenous (A-V) fistula or other type of vascular
access to receive hemodialysis and prolong their lives. The transformation of a vein to a fistula is one of the
most intriguing processes in vascular biology. The desired scenario is that the fistula matures becoming a
larger vessel with increased luminal area and a thicker wall. Unfortunately, A-V fistulas frequently fail (~40%)
because venous stenosis compromises blood flow. We recently discovered that stenosis occurs due to
excessive medial fibrosis, and is aggravated by intimal hyperplasia (IH). Our specific goal is to demonstrate
that up-regulated lysyl oxidase (LOX) in the venous limb of the A-V fistula mediates improper extracellular
matrix (ECM) remodeling and pathological expansion of the intima, which causes stenosis and failure. This
proposal establishes the cause- effect relationship among LOX and fistula outcomes in order to design
targeted therapies. Our proposal is built on strong scientific premises (manuscripts and unique preliminary
data) that suggest a mechanistic relationship between postoperative upregulation of LOX in native fistulas
and the improper remodeling that causes fistula failure. Specifically, we hypothesize that LOX disrupts the
epigenetic marks that secure contractile gene expression in smooth muscle cells (SMC), thereby facilitating
the phenotypic switch of SMCs, neointima formation, and fibrosis of newly created A-V fistulas. We also
postulate that extracellular LOX simultaneously increases stiffness and altered collagen configuration in this
type of vascular access. We will test our hypothesis in three specific aims and five experimental layouts
that will prove: 1) the contribution of vascular LOX to postoperative A-V fistula stenosis; 2) the role of LOX in
the epigenetic control of the SMC phenotype after fistula creation; and 3) the relationship between pre-
existing LOX and A-V fistula outcomes in a human cohort. We will use fine microsurgical techniques in a
novel conditional knockout mice and in vitro and in situ models to successfully achieve our goals. We will
also interrogate a human biorepository of >300 patients undergoing creation of a two- stage brachiobasilic
transposition fistula to search for associations between the levels of LOX and maturation failure. In
conclusion, with the successful accomplishment of this proposal, we are paving the way for the design of
new drugs and cell type-specific interventions to effectively target A-V fistula fibrosis and reduce vascular
access complications.

## Key facts

- **NIH application ID:** 10111340
- **Project number:** 5I01BX004658-02
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** Roberto Irenardo Vazquez Padron
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111340

## Citation

> US National Institutes of Health, RePORTER application 10111340, The Multiple Roles of Lysyl Oxidase in Arteriovenous Fistula Failure (5I01BX004658-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10111340. Licensed CC0.

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